4—氧—8—1对—（4—苯丁氧基）苯甲酰氨基1—2—（5—四唑基）…

在扑尔敏预先处理的致敏豚鼠，白三烯拮抗剂４－氧－８－［对－４－苯丁氧基）苯甲酰氨基］－２－（５－四唑基）－４Ｈ－１－苯并吡喃（ＯＮＯ－１０７８，０．０３，０．３ｍｇ．ｋｇ＾－１，ｉｖ）显著抑制抗原引起的肺内压增高，并完全抑制肺内气道中心部和外周部的依文思蓝渗出，肺内压与这两部位的染料渗出量呈正相关，但与气管和主支气管的染料渗出无相关性，在扑尔敏处理的肺条和气管条，ＯＮＯ－１０７８仅部分抑制抗原诱导     

白三烯拮抗剂ONO－1078对辣椒素和P物质诱导豚鼠支气管收缩和微血管渗漏的作用

目的：探讨白三烯特异性拮抗剂４氧８［对（４苯丁氧基）苯甲酰氨基］２（５四唑基）４Ｈ１苯并吡喃半水合物（ＯＮＯ１０７８）对气道辣椒素敏感的感觉神经功能的调节作用．方法：观察豚鼠肺内压（ＩＰＰ）、伊文思蓝渗出量和离体支气管平滑肌收缩反应．结果：辣椒素（Ｃａｐ，００５ｍｇ·ｋｇ－１，ｉｖ）、Ｐ物质（ＳＰ，１μｇ·ｋｇ－１，ｉｖ）和白三烯Ｃ４（ＬＴＣ４，０５μｇ·ｋｇ－１，ｉｖ）增高ＩＰＰ和支气管及肺内气道伊文思蓝渗出量，ＯＮＯ１０７８（００３ｍｇ·ｋｇ－１，ｉｖ）完全阻断ＬＴＣ４的作用，减弱Ｃａｐ的作用，但不影响ＳＰ的作用．ＯＮＯ１０７８（１μｍｏｌ·Ｌ－１）还显著抑制Ｃａｐ收缩支气管平滑肌，对ＳＰ无效．结论：ＯＮＯ１０７８通过抑制感觉神经肽释放而部分抑制Ｃａｐ的作用．     

速激肽受体拮抗剂对白三烯C_4诱导豚鼠气道收缩和微血管渗漏的作用

本实验探讨了内源性速激肽是否参与白三烯Ｃ４（ＬＴＣ４）的气道效应．ＬＴＣ４（０．５μｇｋｇ－１，ｉｖ）可增高豚鼠肺内压（ＩＰＰ）和气道内依文思蓝渗出。速激肽ＮＫ－１受体拮抗剂ＣＰ－９６３４５｛（２Ｓ，３Ｓ）－顺式－２－（二苯甲基）－Ｎ－［（２－甲氧苯）－甲基］－１－杂氮双环［２．２．２］辛烷－３－胺｝１ｍｇｋｇ－１，ｉｖ，可减弱ＬＴＣ４诱导的依文思蓝渗出；ＮＫ－２受体拮抗剂ＳＲ－４８９６８｛（Ｓ）－Ｎ－甲基－Ｎ－［４－（４－乙酰氨基－４－苯基哌啶）－２－（３，４－二氯苯基）丁基］苯甲酰胺｝，１ｍｇｋｇ－１，ｉｖ，可抑制ＩＰＰ的增高．白三烯拮抗剂ＯＮＯ－１０７８（０．０３ｍｇｋｇ－１，ｉｖ）可阻断这两种反应．结果说明内源性速激肽增强ＬＴＣ４的气道作用，其中ＮＫ－１受体介导微血管渗漏，ＮＫ－２受体介导支气管收缩．     

白三烯拮抗剂ONO—1078对辣椒素和P物质诱导豚鼠支气管收缩和…

目的：探讨白三烯特异性拮抗剂４氧－８－（对－（４－苯丁氧基）苯甲酰氨基）－２－（（５－四唑基）－４Ｈ－１－苯并吡喃半水合物（ＯＮＯ－１０７８）对气道辣椒素敏感的感觉神经功能的调节作用。方法：观察豚鼠肺内压（ＩＰＰ），伊文思蓝渗出量和离体支气管平滑肌收缩反应，结果：辣椒素（Ｃａｐ，０．０５ｍｇ．ｋｇ＾－１，ｉｖ）Ｐ物质（ＳＰ，１μｇ．ｋｇ＾－１，ｉｖ）和白三烯Ｃ４（ＬＴＣ４，０．５μｇ．ｋｇ＾－１）     

白三烯拮抗剂ONO—1078对电刺激迷走神经辣椒素和P物质引起的…

阐明ＯＮＯ－１０７８（ＯＮＯ，４－氧－８［对－（４－苯丁氧基）苯甲酰氨基］－２－（５－四唑基）－４Ｈ－１－苯并吡喃）对神经原性刺激诱导心血管反应的作用。观察豚鼠心房和心室伊文思蓝渗出以及平均主动脉压变化。在阿托品预先处理后，电刺激迷走神经显著增高伊文思蓝渗出；辣椒素和Ｐ物质也增加染料渗出并降低平均动脉压。     

白细胞三烯拮抗剂ONO－1078对豚鼠迷走神经电刺激引起气道痉挛及微血管渗漏作用

阿托品预先处理的豚鼠，电刺激迷走神经（１０Ｈｚ，５ｍｓ，２Ｖ或１０Ｖ，９０ｓ）引起气道阻力增高，气管、主支气管和肺内气道的依文思蓝渗出量增加，并随刺激强度加大而增强。白细胞三烯拮抗剂ＯＮＯ－１０７８（０．０３，０．１ｍｇ·ｋｇ－１，ｉｖ）对气道阻力的增高无明显影响；但显著抑制微血管渗漏，在刺激强度低（２Ｖ）时更明显。结果提示白细胞三烯类参与神经原性炎症时的气道微血管渗漏反应。     

Inhibitory effects of ginkgolides on nitric oxide production in neonatal rat microglia in vitro

目的：观察银杏内酯Ａ和Ｂ，ＰＡＦ拮抗剂阿帕泛（Ａｐａ）和ＮＯＳ抑制剂ＬＮＡ对新生大鼠小胶质细胞（Ｍｉ）产生ＮＯ的影响．方法：以Ｇｒｉｅｓ反应测定亚硝酸盐含量表示ＮＯ量．结果：在静息Ｍｉ，ＧＡ，ＧＢ和Ａｐａ在１－１００００ｎｍｏｌ·Ｌ－１范围对Ｍｉ产生ＮＯ没有影响，但ＬＮＡ可浓度依赖性地抑制ＮＯ产生，其ＩＣ５０（９５％可信限）值为３．４（０．８－１４９）μｍｏｌ·Ｌ－１．而在激活的Ｍｉ，ＧＡ，ＧＢ和ＬＮＡ可浓度依赖性地抑制ＮＯ产生，其ＩＣ５０（９５％可信限）值分别为５．７（１．８－１８１），１．１（０．３－４４）和０．５（０．１－２．８）μｍｏｌ·Ｌ－１，但Ａｐａ不能抑制ＮＯ产生．结论：ＧＡ和ＧＢ抑制ＬＰＳ诱导Ｍｉ产生ＮＯ．     

白三烯拮抗剂ONO-1078对抗原诱导的豚鼠皮肤微血管渗漏的抑制作用

补尔敏预先处理的致敏豚鼠，白三烯拮抗剂ＯＮＯ－１０７８显著抑制抗原引起的依文思蓝在耳廓皮肤的渗出，静脉注射的ＩＤ５０为０．０３５ｍｇ／ｋｇ，腹腔注射为０．３６ｍｇ／ｋｇ，提示白三烯参与皮肤过敏反应，ＯＮＯ－１０７８对过敏性皮肤病变有治疗价值。但静脉注射较大剂量的ＯＮＯ－１０７８可直接引起皮肤微血管渗漏和短暂性血压降低，而腹腔注射无这些作用。     

2,6-二甲基-4-(2-氯苯基)-1,4-二氢-3,5-吡啶二羧酸二甲酯对大鼠野百合碱性肺动脉高压的防治作用

用野百合碱（ＭＣＴ）复制大鼠慢性肺动脉高压（ＰＨ）病理模型，探讨钙拮抗剂２，６－二甲基－４－（２－氯苯基）－１，４－二氢－３，５－吡啶二羧酸二甲酯（ＤＣＤＤＰ）对ＰＨ的防治作用．ＤＣＤＤＰ５，５０，５００μｇ·ｋｇ－１ｉｐ，每日１次，连续２８ｄ；ＭＣＴ６０ｍｇ·ｋｇ－１在第１次给ＤＣＤＤＰ后３０ｍｉｎｓｃ．观察肺血流动力学指标变化，血浆和肺匀浆中内皮素样免疫反应物（ｉｒ－ＥＴ），一氧化氮（ＮＯ）含量，超氧化物歧化酶（ＳＯＤ）活性和丙二醛（ＭＤＡ）含量的改变．三种不同剂量的ＤＣＤＤＰ分别使平均肺动脉压从４．５±０．９ｋＰａ（ＭＣＴ组）降至３．２±０．２，３．５±０．６和３．８±０．９ｋＰａ，肺血管阻力从１１８±１７ｋＰａ·ｍｉｎ－１·Ｌ－１（ＭＣＴ组）降至６５±１６，６８±１８和７６±１８ｋＰａ·ｍｉｎ－１·Ｌ－１（Ｐ＜０．０１），提示在本实验剂量范围内，中，低剂量ＤＣＤＤＰ防治效果似较好．ＤＣＤＤＰ不影响ＭＣＴ性ＰＨ时血浆和肺匀浆中ｉｒ－ＥＴ的改变，但可显著升高肺匀浆中ＮＯ的含量和ＳＯＤ活性，使肺匀浆中ＭＤＡ含量降至正常，这可能是其降低肺动脉压的机理之一．     

4－甲氧基－2－巯基－N－氧化吡啶钠的抗肿瘤及免疫抑制作用

４－个甲氧基－２－巯基－Ｎ－氧化吡啶钠（４－甲氧基巯氧吡啶钠，ＳｏｄｉｕｍＭｅｔｈｏｘｙｐｙｒｉｄｉｎｅｔｈｉｏｎｅ，ＳＭＰＴ）在试管内０．０１ｍｇ·Ｌ－１可抑制多种传代人癌细胞林，抑制细胞有丝分裂和损害细胞膜相结构，单用对动物移植性肿瘤无效，但明显增强氟脲嘧啶对小鼠Ｓ１８０的抑癌作用。使胸腺和脾脏重量明显减轻，抑制ＳＲＢＣ诱导的小鼠血清溶血素反应，抑制ＤＮＣＢ诱导的豚鼠皮肤迟发型超敏反应，抑制ＰＨＡ诱导的大鼠３Ｈ－ＴｄＲ参入的淋巴细胞转化。与２－巯基－Ｎ－氧化吡啶钠（巯氧吡啶钠，ＳｏｄｉｕｍＰｙｒｉｄｉｎｅｔｈｉｏｎｅ．ＳＰＴ）比较，小鼠ＬＤ５０（ｉｐ）增大，而试管内抑瘤的ＩＣ５０相近。     

白细胞三烯拮抗剂ONO-1078对豚鼠迷走神经电刺激引起气道痉挛及微血管渗漏作用

阿托品预先处理的豚鼠,电刺激迷走神经(10Hz,5ms,2V或10V,90s)引起气道阻力增高,气管、主支气管和肺内气道的依文思蓝渗出量增加,并随刺激强度加大而增强。白细胞三烯拮抗剂ONO-1078(0.03,0.1mg·kg^-1,iv)对气道阻力的增高无明显影响;但显著抑制微血管渗漏,在刺激强度低(2V)时更明显。结果提示白细胞三烯类参与神经原性炎症时的气道微血管渗漏反应。     

速激肽受体拮抗剂对白三烯C4诱导豚鼠气道收缩和微血管渗漏的作用

本实验探讨了内源性速激肽是否参与白三烯C₄(LTC₄)的气道效应. LTC₄(0.5 μg·kg^-1, iv)可增高豚鼠肺内压(IPP)和气道内依文思蓝渗出。速激肽NK-1受体拮抗剂CP-96345｛(2S, 3S)-顺式-2-( 二苯甲基)-N-［(2-甲氧苯)-甲基］-1-杂氮双环［2.2.2］辛烷-3-胺｝ 1 mg·kg^-1，iv，可减弱LTC₄诱导的依文思蓝渗出；NK-2受体拮抗剂SR-48968｛(S)-N-甲基-N-［4-(4-乙酰氨基-4-苯基哌啶)-2-(3,4-二氯苯基)丁基］苯甲酰胺｝，1 mg·kg^-1， iv，可抑制IPP的增高. 白三烯拮抗剂ONO-1078 (0.03 mg·kg^-1, iv)可阻断这两种反应. 结果说明内源性速激肽增强 LTC₄的气道作用，其中NK-1受体介导微血管渗漏，NK-2受体介导支气管收缩.     

白三烯拮抗剂ONO-1078对化学物质诱导大鼠皮肤微血管渗漏的抑制作用

大鼠皮内注射组胺、辣椒素和甲醛诱导皮肤微血管渗漏,白三烯拮抗剂ONO-1078剂量依赖性抑制这一反应,ID₅₀分别为1.98,1.78,2.23mg·kg^-1。与扑尔敏相比,对组胺的作用较弱,对辣椒素和甲醛的作用较强,地塞米松的作用强于ONOl078和扑尔敏。ONO-l078还抑制LTD4的作用,对大剂量组胺、缓激肽和P物质无明显作用。ONO-l078的作用可能与抑制感觉神经肽释放有关。     

Differential effects of phosphoramidon on neurokinin A- and substance P-induced airflow obstruction and airway microvascular leakage in guinea-pig.

1. The effects of the inhaled neuropeptides, neurokinin A (NKA) and substance P (SP) on lung resistance (RL) and airway microvascular permeability were studied in anaesthetized guinea-pigs. 2. Single doses of inhaled NKA (3 x 10(-5), 1 x 10(-4), 3 x 10(-4) M; 45 breaths) and SP (1 x 10(-4), 3 x 10(-4), 1 x 10(-3); 45 breaths) caused a dose-dependent increase in both RL and airway microvascular leakage, assessed as extravasation of the albumin marker, Evans blue dye. 3. NKA at 1 x 10(-4) and 3 x 10(-4) M resulted in a significantly higher increase in RL than SP at the same doses. 4. Inhaled SP (3 x 10(-4) M; 45 breaths) caused significantly higher Evans blue dye extravasation in main bronchi and proximal intrapulmonary airways compared to the same dose of NKA. 5. Pretreatment with the specific inhibitor of neural endopeptidase (NEP24.11), phosphoramidon, caused an approximately 100 fold leftward shift of the RL responses to inhaled NKA and SP. 6. Phosphoramidon significantly potentiated both NKA- and SP-induced airway microvascular leakage at proximal intrapulmonary airways, but not at any other airway level. 7. Inhibition of NEP24.11 potentiate both the SP- or NKA-induced airflow obstruction to a larger extent than the induced airway microvascular leakage, suggesting that NEP24.11 is more important in the modulation of the airflow obstruction observed after these mediators.     

咪苯嗪酮对花生四烯酸诱导的大鼠脑血栓形成的影响

花生四烯酸(AA)0.25～1 mg·kg~(-1)经颈内动脉注射能诱发大鼠同侧大脑半球脑内血栓形成,明显增加伊文思蓝通过血脑屏障渗入脑实质的量,峰值为205±s 50 mg·kg~1脑组织,相应对照组为10±s 5mg·kg~1,咪苯嗪酮0.25～0.5mg·kg~1 iv能对抗AA引起的大鼠脑血栓形成,显著降低脑实质内伊文思蓝的含量,作用呈剂量依赖性,且强于哒唑氧苯     

Effects of STA(2), a thromboxane A(2) mimetic, in inducing airflow obstruction and airway microvascular leakage in guinea pigs

BACKGROUND: U-46619, a thromboxane A(2) (TXA(2)) mimetic, is shown to cause airway microvascular leakage, although the effects is weak when comparing with that to induce bronchoconstriction in guinea pigs. OBJECTIVE: In order to know the airway effect of TXA(2) more accurately, we have examined the effects of STA(2), a TXA(2) mimetic with higher affinity to TXA(2) (TP) receptors than U-46619, to induce airway microvascular leakage and airflow obstruction. METHODS: Anesthetized and ventilated guinea pigs were i.v. given STA(2) (3-30 nmol/kg) or U-46619 (3-100 nmol/kg) 1 min after i.v. Evans blue dye. STA(2)- and U-46619-induced increases in lung resistance (R(L)) was measured for 6 min. The amount of extravasated Evans blue dye in the lower airways was, then, examined as an index of leakage. In selected animals, specific TP receptor antagonists (10 microg/kg S-1452 or 10 mg/kg ONO-3708) were pretreated i.v. RESULTS: Both STA(2) and U-46619 induced significant increases in leakage and airflow obstruction. However, STA(2) induced a slow and significantly less increase in R(L) but caused a significantly greater increase in extravasation of Evans blue dye compared to U-46619. Specific TP receptor antagonists completely abolished both airway effects induced by STA(2) and U-46619. CONCLUSION: Our present results have supported a possibility that TXA(2) induces microvascular leakage as well as bronchoconstriction in the airways.     

In vivo pharmacologic profile of ONO-1078: a potent, selective and orally active peptide leukotriene (LT) antagonist.

We investigated the in vivo antagonistic activity of ONO-1078 against peptide leukotrienes (LTs) in guinea pigs. ONO-1078, when administered p.o. (0.3-3 mg/kg), caused a dose-dependent reduction of LTC4-, LTD4- and LTE4-induced bronchoconstriction, LTD4-induced airway microvascular leakage and LTD4-induced increase in cutaneous vascular permeability. When administered intravenously, ONO-1078 (3-30 micrograms/kg) inhibited these responses approximately 200-600 fold more potently than FPL55712. When guinea pigs were treated with indomethacin to examine the antagonism of ONO-1078 on the direct action against peptide LTs, intravenous (3-30 micrograms/kg) and oral (0.3-3 mg/kg) administration of ONO-1078 also inhibited LTC4- and LTD4-induced bronchoconstriction, and its activity was approximately 300-500 fold more potent than that of FPL55712. ONO-1078 (10 mg/kg, i.v.) had no inhibitory effect on bronchoconstrictions induced by histamine, acetylcholine, serotonin, arachidonic acid, LTB4, prostaglandin (PG) F2 alpha, PGD2, 9 alpha, 11 beta-PGF2, a stable thromboxane A2 mimetic agent and platelet activating factor. Furthermore, oral administration of ONO-1078 (1-10 mg/kg) inhibited slow-reacting substance of anaphylaxis mediated bronchoconstriction induced by antigen in a dose-dependent manner. These results indicate that ONO-1078 is an extremely potent, selective and orally active peptide LT antagonist and that oral administration of ONO-1078 antagonizes not only exogenously administered peptide LTs but also endogenous peptide LTs.     

Leukotriene D4- and prostaglandin F2 alpha-induced airflow obstruction and airway plasma exudation in guinea-pig: role of thromboxane and its receptor.

1. We studied the effects of a thromboxane A2 receptor (TP receptor) antagonist, ICI-192,605 (0.5 mg kg-1, i.v.) and a selective thromboxane (Tx) synthetase inhibitor, OKY-046 (30 mg kg-1, i.v.), on airway responses induced by leukotriene D4 (LTD4; 0.2 nmol) or prostaglandin F2 alpha (PGF2 alpha; 20 nmol) instilled via the airways route to anaesthetized guinea-pigs. For a comparison, airway responses to a TxA2-mimetic, U-46619 (0.02 nmol) were also studied. We measured both lung resistance (RL) to monitor airflow obstruction, and extravasation of Evans Blue dye to quantify airway plasma exudation. 2. Instilled LTD4 into the tracheal lumen induced an immediate peak and subsequently persistent increase in RL and produced a large amount of extravasation of Evans Blue dye at all airway levels. Both ICI-192,605 and OKY-046 significantly attenuated the persistent increase in RL following the immediate response and reduced LTD4-induced extravasation of Evans Blue dye in the trachea and proximal intrapulmonary airway. Instilled LTD4 produced significant increases in immunoreactive TxB2 in bronchoalveolar lavage fluid obtained 1.5 min after instillation of LTD4. 3. Instilled PGF2 alpha into the tracheal lumen induced an immediate increase in RL which peaked at approximately 15 s. We also observed a delayed sustained increase in RL, reaching a second peak at approximately 4 min. PGF2 alpha produced small but significant increases in the amount of Evans Blue dye at all airway levels. As with PGF2 alpha, instillation of U-46619 produced a biphasic increase in RL and extravasation of Evans Blue dye.(ABSTRACT TRUNCATED AT 250 WORDS)